Sepsis continues to be a major cause of death following shock, trauma and burns. Cardiac performance during sepsis has been intensively investigated with disparate results. Recently, the use of load independent assessments of cardiac contractility such as end-systolic pressure-volume relationship have indicated depressed inotropity during acute endotoxemia. Our previous studies indicate that animals which survive acute endotoxemia exhibited no depression of cardiac contractility whereas nonsurviving animals exhibited a marked depression. These data suggest that cardiac contractile failure could be a determinant of nonsurvival following acute endotoxemia. Furthermore, this study revealed that depressed cardiac contractile function was associated with a relative reduction in myocardial blood flow. Since clinical sepsis can persist for several days, this study will use a method to produce chronic endotoxemia. In our pilot studies, we implanted an endotoxin loaded osmotic infusion pump into a chronically instrumented pig so that endotoxin was infused i.v. over 4 days. This pig exhibited a 2 day "hyperdynamic" state followed by a "hypodynamic" state. The "hyperdynamic" state was characterized by elevated systolic pressure, dP/dt and rate and reduced contractility as indicated by end systolic pressure-wall thickness relationship. This project will study the effect of chronic endotoxemia upon cardiac systolic and diastolic function in chronically instrumented pigs. We will characterize the relationship of global and regional myocardial perfusion to systolic and diastolic function. We will then test the hypothesis that the compromise of cardiac systolic and diastolic function is caused by myocardial underperfusion by determining if pharmacological augmentation of myocardial perfusion via administration of alpha adrenergic receptor blockade or direct coronary vasodilation (via dipyridamole) will attentuate the deterioration of cardiac function induced by chronic endotoxemia. Future studies will determine if reversal of myocardial flow deficit and presumably restoration of cardiac function can forestall the conversion of "hyperdynamic" to "hypodynamic" endotoxemia.